Targeting CDCP1 dimerization in triple-negative breast cancer.
Targeting CDCP1 dimerization in triple-negative breast cancer.
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靶向三阴性乳腺癌中的 CDCP1 二聚化。
DOI：
10.1080/15384101.2016.1204849
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Razorenova,OlgaV
中科院分区：
文献类型：
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作者：
Wright,HeatherJ;Police,AliceM;Razorenova,OlgaV
在美国，乳腺癌是新发癌症病例的主要贡献者，也是女性癌症死亡的第二大原因。大约15%的乳腺癌患者患有三阴性乳腺癌（TNBC）疾病。TNBC缺乏雌激素（ER）、孕激素（PR）和人表皮生长因子2（HER 2）受体的表达，使其分别对目前FDA批准的乳腺癌靶向治疗（如他莫昔芬、芳香酶抑制剂和曲妥珠单抗（赫赛汀））具有抗性。针对其他受体酪氨酸激酶（RTK）途径的临床试验，如表皮生长因子受体（EGFR，也称为HER 1）与西妥昔单抗和血管内皮生长因子A（VEGF-A）与贝伐单抗联合标准治疗化疗，结果并不令人印象深刻。1目前的临床试验正在研究免疫调节治疗剂如pembrolizumab，nivolumab和ipilimumab以及靶向雄激素受体和PI 3 K通路的治疗剂的疗效。因此，由于TNBC通常比非TNBC更具侵袭性，具有更高的复发和转移率，因此重要的是绘制新的治疗靶点以治疗TNBC进展和转移。TNBC过表达跨膜蛋白，含CUB结构域的蛋白1（CDCP 1），2，3，据报道在多种体内模型中驱动转移。4毫不奇怪，已知会引发转移的缺氧微环境在肾癌中的mRNA和蛋白质水平上调CDCP 1，5并刺激TNBC中的CDCP 1磷酸化，增加其活性。2 CDCP 1含有一个大的胞外结构域，具有3个CUB结构域，对蛋白质-蛋白质相互作用很重要。6 CDCP 1胞外结构域可被丝氨酸蛋白酶切割，产生含有CUB 1的65 kDa片段，其释放到胞外空间中，以及含有CUB 2和CUB 3的75 kDa膜结合同种型，称为切割的CDCP 1（cCDCP 1）。4重要的是，cCDCP 1代表CDCP 1的活性形式，与全长CDCP 1相比，其通过多种激酶有效地刺激信号传导，包括PKCd、MAPK、ERK和Akt，4，7。在我们最近发表在Oncogene Journal 2上的文章中，我们报道了TNBC表达高水平的磷酸化cCDCP 1，形成同源二聚体。cCDCP 1的可溶性细胞外片段抑制cCDCP 1二聚化及其下游信号传导的能力强调了同源二聚化对CDCP 1活性的重要性。该cCDCP 1片段降低PKCd磷酸化，在2D中抑制TNBC迁移，在3D水凝胶中抑制侵袭和增殖并增加凋亡。因此，迄今为止，CDCP 1激活级联包括3个水平：磷酸化、切割和二聚化。目前开发了抑制CDCP 1切割的抗体治疗剂。7还有能够间接抑制CDCP 1裂解的治疗剂，例如地塞米松，3类固醇治疗剂和抑肽酶（特雷西洛）（NCT 00354900，晚期乳腺癌试验终止）。然而，最后2种治疗剂具有显著的脱靶效应。特别是类固醇不仅降低患者的生活质量，而且还可能导致高血压和高血糖等疾病，这增加了合并症的风险。我们发现cCDCP 1胞外域参与二聚化，为治疗开发开辟了新途径。这种方法被多种成功的FDA批准的疗法证明是合理的，这些疗法抑制了驱动肿瘤进展的细胞表面受体的同源和异源二聚化。这些措施包括.
Breast cancer is the leading contributor to new cancer cases and the second leading cause of cancer deaths in women in the United States. Approximately 15% of breast cancer patients present with triple-negative breast cancer (TNBC) disease. TNBC lacks expression of the Estrogen (ER), Progesterone (PR), and Human Epidermal growth factor 2 (HER2) receptors, rendering it resistant to current FDA-approved breast cancer targeted therapies like tamoxifen, aromatase inhibitors, and trastuzumab (Herceptin), respectively. Clinical trials targeting other Receptor Tyrosine Kinase (RTK) pathways like Epidermal Growth Factor Receptor (EGFR, also known as HER1) with cetuximab and Vascular Endothelial Growth Factor A (VEGF-A) with bevacizumab in combination with standard-of-care chemotherapy gave unimpressive results. 1 Current clinical trials are now investigating the efficacy of immune-modulating therapeutics like pembrolizumab, nivolumab, and ipilimumab, as well as therapeutics targeting androgen receptor and PI3K pathway. Thus, because TNBC is typically more aggressive with higher rates of recurrence and metastasis than non-TNBC, it is important to map new therapeutic targets to treat TNBC progression and metastasis. TNBC overexpresses a trans-membrane protein, CUB-domain containing protein 1 (CDCP1), 2, 3 reported to drive metastasis in multiple in vivo models. 4 Not surprisingly, a hypoxic microenvironment, known to trigger metastasis, upregulates CDCP1 at the mRNA and protein level in kidney cancer, 5 and stimulates CDCP1 phosphorylation in TNBC, increasing its activity. 2 CDCP1 contains a large extracellular domain with 3 CUB domains, important for protein-protein interactions. 6 CDCP1s extracellular domain can be cleaved by serine proteases resulting in a 65 kDa fragment containing CUB1 that is released into the extracellular space and a 75 kDa membrane-bound isoform containing CUB2 and CUB3, referred as cleaved CDCP1 (cCDCP1). 4 Importantly, cCDCP1 represents an active form of CDCP1, which efficiently stimulates signaling through multiple kinases, including PKCd, MAPK, ERK, and Akt, 4, 7 in comparison to the full length CDCP1. In our recent publication in Oncogene Journal 2 we reported that TNBC expresses high levels of phosphorylated cCDCP1 that forms a homo-dimer. The importance of homo-dimerization for CDCP1s activity was underscored by the ability of a soluble extracellular fragment of cCDCP1 to inhibit dimerization of cCDCP1 and its downstream signaling. This cCDCP1 fragment decreased PKCd phosphorylation, inhibited TNBC migration in 2D, inhibited invasion and proliferation and increased apoptosis in 3D hydrogels. Thus, to date, the CDCP1 activation cascade includes 3 levels: phosphorylation, cleavage, and dimerization. Currently there are antibody therapeutics developed that inhibit CDCP1 cleavage. 7 There are also therapeutics capable of indirect inhibition of CDCP1 cleavage, such as dexamethasone, 3 a steroid therapeutic, and aprotinin (Trasylol)(NCT00354900, trial in advanced breast cancer terminated). However, the last 2 therapeutics have substantial off-target effects. Steroids in particular not only decrease patient quality of life, but may also cause disease conditions like hypertension and hyperglycemia, which increase the risk of co-morbidities. Our discovery of the involvement of cCDCP1 extracellular domain in dimerization opens up a new avenue for therapeutic development. This approach is justified by multiple successful FDA-approved therapies that inhibit homo-and hetero-dimerization of cell surface receptors driving tumor progression. These include …